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1.
Eur Psychiatry ; 64(1): e14, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33517931

RESUMO

BACKGROUND: Systemic inflammation has been linked with mood disorder and cognitive impairment. The extent of this relationship remains uncertain, with the effects of serum inflammatory biomarkers compared to genetic predisposition toward inflammation yet to be clearly established. METHODS: We investigated the magnitude of associations between C-reactive protein (CRP) measures, lifetime history of bipolar disorder or major depression, and cognitive function (reaction time and visuospatial memory) in 84,268 UK Biobank participants. CRP was measured in serum and a polygenic risk score for CRP was calculated, based on a published genome-wide association study. Multiple regression models adjusted for sociodemographic and clinical confounders. RESULTS: Increased serum CRP was significantly associated with mood disorder history (Kruskal-Wallis H = 196.06, p < 0.001, η2 = 0.002) but increased polygenic risk for CRP was not (F = 0.668, p = 0.648, η2 < 0.001). Compared to the lowest quintile, the highest serum CRP quintile was significantly associated with both negative and positive differences in cognitive performance (fully adjusted models: reaction time B = -0.030, 95% CI = -0.052, -0.008; visuospatial memory B = 0.066, 95% CI = 0.042, 0.089). More severe mood disorder categories were significantly associated with worse cognitive performance and this was not moderated by serum or genetic CRP level. CONCLUSIONS: In this large cohort study, we found that measured inflammation was associated with mood disorder history, but genetic predisposition to inflammation was not. The association between mood disorder and worse cognitive performance was very small and did not vary by CRP level. The inconsistent relationship between CRP measures and cognitive performance warrants further study.

2.
Sci Rep ; 11(1): 632, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436761

RESUMO

Understanding why individuals with severe mental illness (Schizophrenia, Bipolar Disorder and Major Depressive Disorder) have increased risk of cardiometabolic disease (including obesity, type 2 diabetes and cardiovascular disease), and identifying those at highest risk of cardiometabolic disease are important priority areas for researchers. For individuals with European ancestry we explored whether genetic variation could identify sub-groups with different metabolic profiles. Loci associated with schizophrenia, bipolar disorder and major depressive disorder from previous genome-wide association studies and loci that were also implicated in cardiometabolic processes and diseases were selected. In the IMPROVE study (a high cardiovascular risk sample) and UK Biobank (general population sample) multidimensional scaling was applied to genetic variants implicated in both psychiatric and cardiometabolic disorders. Visual inspection of the resulting plots used to identify distinct clusters. Differences between these clusters were assessed using chi-squared and Kruskall-Wallis tests. In IMPROVE, genetic loci associated with both schizophrenia and cardiometabolic disease (but not bipolar disorder or major depressive disorder) identified three groups of individuals with distinct metabolic profiles. This grouping was replicated within UK Biobank, with somewhat less distinction between metabolic profiles. This work focused on individuals of European ancestry and is unlikely to apply to more genetically diverse populations. Overall, this study provides proof of concept that common biology underlying mental and physical illness may help to stratify subsets of individuals with different cardiometabolic profiles.

3.
Genes (Basel) ; 11(11)2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33182605

RESUMO

Individuals with severe mental illness have an increased risk of cardiometabolic diseases compared to the general population. Shared risk factors and medication effects explain part of this excess risk; however, there is growing evidence to suggest that shared biology (including genetic variation) is likely to contribute to comorbidity between mental and physical illness. Contactins are a family of genes involved in development of the nervous system and implicated, though genome-wide association studies, in a wide range of psychological, psychiatric and cardiometabolic conditions. Contactins are plausible candidates for shared pathology between mental and physical health. We used data from UK Biobank to systematically assess how genetic variation in contactin genes was associated with a wide range of psychological, psychiatric and cardiometabolic conditions. We also investigated whether associations for cardiometabolic and psychological traits represented the same or distinct signals and how the genetic variation might influence the measured traits. We identified: A novel genetic association between variation in CNTN1 and current smoking; two independent signals in CNTN4 for BMI; and demonstrated that associations between CNTN5 and neuroticism were distinct from those between CNTN5 and blood pressure/HbA1c. There was no evidence that the contactin genes contributed to shared aetiology between physical and mental illness.

4.
J Affect Disord ; 279: 316-323, 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33096330

RESUMO

BACKGROUND: The association between loneliness and suicide is poorly understood. We investigated how living alone, loneliness and emotional support were related to suicide and self-harm in a longitudinal design. METHODS: Between 2006 and 2010 UK Biobank recruited and assessed in detail over 0.5 million people in middle age. Data were linked to prospective hospital admission and mortality records. Adjusted Cox regression models were used to investigate relationships between living arrangements, loneliness and emotional support, and both suicide and self-harm as outcomes. RESULTS: For men, both living alone (Hazard Ratio (HR) 2.16, 95%CI 1.51-3.09) and living with non-partners (HR 1.80, 95%CI 1.08-3.00) were associated with death by suicide, independently of loneliness, which had a modest relationship with suicide (HR 1.43, 95%CI 0.1.01-2.03). For women, there was no evidence that living arrangements, loneliness or emotional support were associated with death by suicide. Associations between living alone and self-harm were explained by health for women, and by health, loneliness and emotional support for men. In fully adjusted models, loneliness was associated with hospital admissions for self-harm in both women (HR 1.89, 95%CI 1.57-2.28) and men (HR 1.74, 95%CI 1.40-2.16). LIMITATIONS: Loneliness and emotional support were operationalized using single item measures. CONCLUSIONS: For men - but not for women - living alone or living with a non-partner increased the risk of suicide, a finding not explained by subjective loneliness. Overall, loneliness may be more important as a risk factor for self-harm than for suicide. Loneliness also appears to lessen the protective associations of cohabitation.

5.
Brain Neurosci Adv ; 4: 2398212820961704, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33088920

RESUMO

Polymorphisms in the apolipoprotein E (APOE) gene have been associated with individual differences in cognition, brain structure and brain function. For example, the ε4 allele has been associated with cognitive and brain impairment in old age and increased risk of dementia, while the ε2 allele has been claimed to be neuroprotective. According to the 'antagonistic pleiotropy' hypothesis, these polymorphisms have different effects across the lifespan, with ε4, for example, postulated to confer benefits on cognitive and brain functions earlier in life. In this stage 2 of the Registered Report - https://osf.io/bufc4, we report the results from the cognitive and brain measures in the Cambridge Centre for Ageing and Neuroscience cohort (www.cam-can.org). We investigated the antagonistic pleiotropy hypothesis by testing for allele-by-age interactions in approximately 600 people across the adult lifespan (18-88 years), on six outcome variables related to cognition, brain structure and brain function (namely, fluid intelligence, verbal memory, hippocampal grey-matter volume, mean diffusion within white matter and resting-state connectivity measured by both functional magnetic resonance imaging and magnetoencephalography). We found no evidence to support the antagonistic pleiotropy hypothesis. Indeed, Bayes factors supported the null hypothesis in all cases, except for the (linear) interaction between age and possession of the ε4 allele on fluid intelligence, for which the evidence for faster decline in older ages was ambiguous. Overall, these pre-registered analyses question the antagonistic pleiotropy of APOE polymorphisms, at least in healthy adults.

6.
J Hypertens ; 38(12): 2482-2489, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32665523

RESUMO

OBJECTIVE: To test for associations between SBP and BMI, with domain-specific cognitive abilities and examine which brain structural phenotypes mediate those associations. METHODS: Using cross-sectional UK Biobank data (final N = 28 412), we examined SBP/BMI vs. cognitive test scores of pairs-matching, matrix completion, trail making test A/B, digit symbol substitution, verbal-numerical reasoning, tower rearranging and simple reaction time. We adjusted for potential confounders of age, sex, deprivation, medication, apolipoprotein e4 genotype, smoking, population stratification and genotypic array. We tested for mediation via multiple structural brain imaging phenotypes and corrected for multiple testing with false discovery rate. RESULTS: We found positive associations for higher BMI with worse reaction time, reasoning, tower rearranging and matrix completion tasks by 0.024-0.067 SDs per BMI SD (all P < 0.001). Higher SBP was associated with worse reasoning (0.034 SDs) and matrix completion scores (-0.024 SDs; both P < 0.001). Both BMI and SBP were associated with multiple brain structural metrics including total grey/white matter volumes, frontal lobe volumes, white matter tract integrity and white matter hyperintensity volumes: specific metrics mediated around one-third of the associations with cognition. CONCLUSION: Our findings add to the body of evidence that addressing cardiovascular risk factors may also preserve cognitive function, via specific aspects of brain structure.

7.
J Alzheimers Dis ; 76(4): 1541-1551, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32651323

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition where the underlying etiology is still unclear. Investigating the potential influence of apolipoprotein E (APOE), a major genetic risk factor, on common blood biomarkers could provide a greater understanding of the mechanisms of AD and dementia risk. OBJECTIVE: Our objective was to conduct the largest (to date) single-protocol investigation of blood biomarkers in the context of APOE genotype, in UK Biobank. METHODS: After quality control and exclusions, data on 395,769 participants of White European ancestry were available for analysis. Linear regressions were used to test potential associations between APOE genotypes and biomarkers. RESULTS: Several biomarkers significantly associated with APOEɛ4 'risk' and ɛ2 'protective' genotypes (versus neutral ɛ3/ɛ3). Most associations supported previous data: for example, ɛ4 genotype was associated with elevated low-density lipoprotein cholesterol (LDL) (standardized beta [b] = 0.150 standard deviations [SDs] per allele, p < 0.001) and ɛ2 with lower LDL (b = -0.456 SDs, p < 0.001). There were however instances of associations found in unexpected directions: e.g., ɛ4 and increased insulin-like growth factor (IGF-1) (b = 0.017, p < 0.001) where lower levels have been previously suggested as an AD risk factor. CONCLUSION: These findings highlight biomarker differences in non-demented people at genetic risk for dementia. The evidence herein supports previous hypotheses of involvement from cardiometabolic and neuroinflammatory pathways.

10.
BMC Med ; 18(1): 97, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32326961

RESUMO

BACKGROUND: Recent efforts to address the obesity epidemic have focused on sugar consumption, especially sugar-sweetened beverages. However, sugar takes many forms, is only one contributor to overall energy consumption and is correlated with other health-related lifestyle factors. The objective was to investigate the associations with all-cause mortality of sugar- and artificially sweetened beverages and naturally sweet juices. METHODS: Setting: UK Biobank, UK. Participants joined the UK Biobank study from 2006 to 2010 and were followed up until 2016; 198,285 men and women aged 40-69 years were eligible for this study (40% of the UK Biobank), of whom 3166 (1.6%) died over a mean of 7 years follow-up. DESIGN: prospective population-based cohort study. Exposure variables: dietary consumption of sugar-sweetened beverages, artificially sweetened beverages, naturally sweet juices (100% fruit/vegetable juices) and total sugar intake, self-reported via 24-h dietary assessment tool completed between 2009 and 2012. MAIN OUTCOME: all-cause mortality. Cox regression analyses were used to study the association between the daily intake of the above beverages and all-cause mortality. Models were adjusted for sociodemographic, economic, lifestyle and dietary confounders. RESULTS: Total energy intake, total sugar intake and percentage of energy derived from sugar were comparable among participants who consumed > 2/day sugar-sweetened beverages and > 2/day fruit/vegetable juices (10,221 kJ/day versus 10,381 kJ/day; 183 g versus 190 g; 30.6% versus 31.0%). All-cause mortality was associated with total sugar intake (highest quintile adj. HR 1.28, 95% CI 1.06-1.55) and intake of sugar-sweetened beverages (> 2/day adj. HR 1.84, 95% CI 1.42-2.37) and remained so in sensitivity analyses. An association between artificially sweetened beverage intake and mortality did not persist after excluding deaths in the first 2 years of follow-up (landmark analysis) nor after excluding participants with recent weight loss. Furthermore, the inverse association between fruit/vegetable juice intake and mortality did not persist after additional adjustment for a diet quality score. CONCLUSIONS: Higher mortality is associated with sugar-sweetened beverages specifically. The lack of an adverse association with fruit/vegetable juices suggests that source of sugar may be important and the association with artificially sweetened beverage may reflect reverse causation.

11.
Mayo Clin Proc ; 95(5): 879-888, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32299669

RESUMO

OBJECTIVE: To investigate whether the addition of grip strength and/or self-reported walking pace to established cardiovascular disease (CVD) risk scores improves their predictive abilities. PATIENTS AND METHODS: A total of 406,834 participants from the UK Biobank, with baseline measurements between March 13, 2006, and October 1, 2010, without CVD at baseline were included in this study. Associations of grip strength and walking pace with CVD outcomes were investigated using Cox models adjusting for classical risk factors (as included in established risk scores), and predictive utility was determined by changes in C-index and categorical net reclassification index. RESULTS: Over a median of 8.87 years of follow-up (interquartile range 3, 8.25-9.47 years), there were 7274 composite fatal/nonfatal events (on the basis of the American College of Cardiology/American Heart Association [ACC/AHA] outcome) and 1955 fatal events (on the basis of the Systematic Coronary Risk Evaluation [SCORE] risk score). Both grip strength and walking pace were inversely associated with CVD outcomes after adjusting for classical risk factors. Addition of grip strength (change in C-index: ACC/AHA, +0.0017; SCORE, +0.0047), usual walking pace (ACC/AHA, +0.0031; SCORE, +0.0130), and both combined (ACC/AHA, +0.0041; SCORE, +0.0148) improved the C-index and also improved the net reclassification index (grip, +0.55%; walking pace, +0.53%; combined, 1.12%). CONCLUSION: The present study has found that the addition of grip strength or usual walking pace to existing risk scores results in improved CVD risk prediction, with an additive effect when both are added. As both these measures are cheap and easy to administer, these tools could provide an important addition to CVD risk screening, although further external validation is required.


Assuntos
Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/fisiopatologia , Força da Mão , Velocidade de Caminhada , Adulto , Bancos de Espécimes Biológicos , Doenças Cardiovasculares/epidemiologia , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Reino Unido/epidemiologia
12.
BMJ ; 368: m336, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32161038

RESUMO

OBJECTIVE: To determine whether bicycle commuting is associated with risk of injury. DESIGN: Prospective population based study. SETTING: UK Biobank. PARTICIPANTS: 230 390 commuters (52.1% women; mean age 52.4 years) recruited from 22 sites across the UK compared by mode of transport used (walking, cycling, mixed mode versus non-active (car or public transport)) to commute to and from work on a typical day. MAIN OUTCOME MEASURE: First incident admission to hospital for injury. RESULTS: 5704 (2.5%) participants reported cycling as their main form of commuter transport. Median follow-up was 8.9 years (interquartile range 8.2-9.5 years), and overall 10 241 (4.4%) participants experienced an injury. Injuries occurred in 397 (7.0%) of the commuters who cycled and 7698 (4.3%) of the commuters who used a non-active mode of transport. After adjustment for major confounding sociodemographic, health, and lifestyle factors, cycling to work was associated with a higher risk of injury compared with commuting by a non-active mode (hazard ratio 1.45, 95% confidence interval 1.30 to 1.61). Similar trends were observed for commuters who used mixed mode cycling. Walking to work was not associated with a higher risk of injury. Longer cycling distances during commuting were associated with a higher risk of injury, but commute distance was not associated with injury in non-active commuters. Cycle commuting was also associated with a higher number of injuries when the external cause was a transport related incident (incident rate ratio 3.42, 95% confidence interval 3.00 to 3.90). Commuters who cycled to work had a lower risk of cardiovascular disease, cancer, and death than those who did not. If the associations are causal, an estimated 1000 participants changing their mode of commuting to include cycling for 10 years would result in 26 additional admissions to hospital for a first injury (of which three would require a hospital stay of a week or longer), 15 fewer first cancer diagnoses, four fewer cardiovascular disease events, and three fewer deaths. CONCLUSION: Compared with non-active commuting to work, commuting by cycling was associated with a higher risk of hospital admission for a first injury and higher risk of transport related incidents specifically. These risks should be viewed in context of the health benefits of active commuting and underscore the need for a safer infrastructure for cycling in the UK.


Assuntos
Ciclismo/lesões , Hospitalização/estatística & dados numéricos , Transportes , Adulto , Idoso , Doenças Cardiovasculares/prevenção & controle , Causas de Morte , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/prevenção & controle , Estudos Prospectivos , Fatores de Risco , Reino Unido/epidemiologia , Caminhada
13.
Mol Psychiatry ; 25(7): 1430-1446, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31969693

RESUMO

Depression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of genetic risk factors, is complex and poorly understood. When modelling trauma exposure as an environmental influence on depression, both gene-environment correlations and gene-environment interactions have been observed. The UK Biobank concurrently assessed Major Depressive Disorder (MDD) and self-reported lifetime exposure to traumatic events in 126,522 genotyped individuals of European ancestry. We contrasted genetic influences on MDD stratified by reported trauma exposure (final sample size range: 24,094-92,957). The SNP-based heritability of MDD with reported trauma exposure (24%) was greater than MDD without reported trauma exposure (12%). Simulations showed that this is not confounded by the strong, positive genetic correlation observed between MDD and reported trauma exposure. We also observed that the genetic correlation between MDD and waist circumference was only significant in individuals reporting trauma exposure (rg = 0.24, p = 1.8 × 10-7 versus rg = -0.05, p = 0.39 in individuals not reporting trauma exposure, difference p = 2.3 × 10-4). Our results suggest that the genetic contribution to MDD is greater when reported trauma is present, and that a complex relationship exists between reported trauma exposure, body composition, and MDD.

14.
Diabetes Care ; 43(2): 440-445, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31852727

RESUMO

OBJECTIVE: HbA1c levels are increasingly measured in screening for diabetes; we investigated whether HbA1c may simultaneously improve cardiovascular disease (CVD) risk assessment, using QRISK3, American College of Cardiology/American Heart Association (ACC/AHA), and Systematic COronary Risk Evaluation (SCORE) scoring systems. RESEARCH DESIGN AND METHODS: UK Biobank participants without baseline CVD or known diabetes (n = 357,833) were included. Associations of HbA1c with CVD was assessed using Cox models adjusting for classical risk factors. Predictive utility was determined by the C-index and net reclassification index (NRI). A separate analysis was conducted in 16,596 participants with known baseline diabetes. RESULTS: Incident fatal or nonfatal CVD, as defined in the QRISK3 prediction model, occurred in 12,877 participants over 8.9 years. Of participants, 3.3% (n = 11,665) had prediabetes (42.0-47.9 mmol/mol [6.0-6.4%]) and 0.7% (n = 2,573) had undiagnosed diabetes (≥48.0 mmol/mol [≥6.5%]). In unadjusted models, compared with the reference group (<42.0 mmol/mol [<6.0%]), those with prediabetes and undiagnosed diabetes were at higher CVD risk: hazard ratio (HR) 1.83 (95% CI 1.69-1.97) and 2.26 (95% CI 1.96-2.60), respectively. After adjustment for classical risk factors, these attenuated to HR 1.11 (95% CI 1.03-1.20) and 1.20 (1.04-1.38), respectively. Adding HbA1c to the QRISK3 CVD risk prediction model (C-index 0.7392) yielded a small improvement in discrimination (C-index increase of 0.0004 [95% CI 0.0001-0.0007]). The NRI showed no improvement. Results were similar for models based on the ACC/AHA and SCORE risk models. CONCLUSIONS: The near twofold higher unadjusted risk for CVD in people with prediabetes is driven mainly by abnormal levels of conventional CVD risk factors. While HbA1c adds minimally to cardiovascular risk prediction, those with prediabetes should have their conventional cardiovascular risk factors appropriately measured and managed.


Assuntos
Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Hemoglobina A Glicada/metabolismo , Estado Pré-Diabético/sangue , Estado Pré-Diabético/epidemiologia , Adulto , Idoso , Bancos de Espécimes Biológicos/estatística & dados numéricos , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Estudos de Coortes , Complicações do Diabetes/sangue , Complicações do Diabetes/epidemiologia , Diabetes Mellitus/sangue , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/etiologia , Feminino , Hemoglobina A Glicada/análise , Humanos , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/diagnóstico , Fatores de Risco , Reino Unido/epidemiologia
15.
Arterioscler Thromb Vasc Biol ; 40(2): 446-461, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31801372

RESUMO

OBJECTIVE: Atherosclerosis is the underlying cause of most cardiovascular disease, but mechanisms underlying atherosclerosis are incompletely understood. Ultrasound measurement of the carotid intima-media thickness (cIMT) can be used to measure vascular remodeling, which is indicative of atherosclerosis. Genome-wide association studies have identified many genetic loci associated with cIMT, but heterogeneity of measurements collected by many small cohorts have been a major limitation in these efforts. Here, we conducted genome-wide association analyses in UKB (UK Biobank; N=22 179), the largest single study with consistent cIMT measurements. Approach and Results: We used BOLT-LMM software to run linear regression of cIMT in UKB, adjusted for age, sex, and genotyping chip. In white British participants, we identified 5 novel loci associated with cIMT and replicated most previously reported loci. In the first sex-specific analyses of cIMT, we identified a locus on chromosome 5, associated with cIMT in women only and highlight VCAN as a good candidate gene at this locus. Genetic correlations with body mass index and glucometabolic traits were also observed. Two loci influenced risk of ischemic heart disease. CONCLUSIONS: These findings replicate previously reported associations, highlight novel biology, and provide new directions for investigating the sex differences observed in cardiovascular disease presentation and progression.


Assuntos
Bancos de Espécimes Biológicos/estatística & dados numéricos , Doenças Cardiovasculares/genética , Artérias Carótidas/diagnóstico por imagem , Espessura Intima-Media Carotídea , Predisposição Genética para Doença , Obesidade/genética , Remodelação Vascular/fisiologia , Índice de Massa Corporal , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/etiologia , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/epidemiologia , Fenótipo , Medição de Risco , Fatores de Risco , Reino Unido/epidemiologia
16.
Brain Imaging Behav ; 14(5): 1468-1476, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30903549

RESUMO

Apolipoprotein (APOE) e4 genotype is an accepted risk factor for accelerated cognitive aging and dementia, though its neurostructural substrates are unclear. The deleterious effects of this genotype on brain structure may increase in magnitude into older age. This study aimed to investigate in UK Biobank the association between APOE e4 allele presence vs. absence and brain imaging variables that have been associated with worse cognitive abilities; and whether this association varies by cross-sectional age. We used brain magnetic resonance imaging (MRI) and genetic data from a general-population cohort: the UK Biobank (N = 8395 after exclusions). We adjusted for the covariates of age in years, sex, Townsend social deprivation scores, smoking history and cardiometabolic diseases. There was a statistically significant association between APOE e4 genotype and increased (i.e. worse) white matter (WM) hyperintensity volumes (standardised beta = 0.088, 95% confidence intervals = 0.036 to 0.139, P = 0.001), a marker of poorer cerebrovascular health. There were no associations with left or right hippocampal, total grey matter (GM) or WM volumes, or WM tract integrity indexed by fractional anisotropy (FA) and mean diffusivity (MD). There were no statistically significant interactions with age. Future research in UK Biobank utilising intermediate phenotypes and longitudinal imaging hold significant promise for this area, particularly pertaining to APOE e4's potential link with cerebrovascular contributions to cognitive aging.

17.
Mol Psychiatry ; 25(11): 3091-3099, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31168069

RESUMO

Genome-wide association studies (GWAS) of psychiatric phenotypes have tended to focus on categorical diagnoses, but to understand the biology of mental illness it may be more useful to study traits which cut across traditional boundaries. Here, we report the results of a GWAS of mood instability as a trait in a large population cohort (UK Biobank, n = 363,705). We also assess the clinical and biological relevance of the findings, including whether genetic associations show enrichment for nervous system pathways. Forty six unique loci associated with mood instability were identified with a SNP heritability estimate of 9%. Linkage Disequilibrium Score Regression (LDSR) analyses identified genetic correlations with Major Depressive Disorder (MDD), Bipolar Disorder (BD), Schizophrenia, anxiety, and Post Traumatic Stress Disorder (PTSD). Gene-level and gene set analyses identified 244 significant genes and 6 enriched gene sets. Tissue expression analysis of the SNP-level data found enrichment in multiple brain regions, and eQTL analyses highlighted an inversion on chromosome 17 plus two brain-specific eQTLs. In addition, we used a Phenotype Linkage Network (PLN) analysis and community analysis to assess for enrichment of nervous system gene sets using mouse orthologue databases. The PLN analysis found enrichment in nervous system PLNs for a community containing serotonin and melatonin receptors. In summary, this work has identified novel loci, tissues and gene sets contributing to mood instability. These findings may be relevant for the identification of novel trans-diagnostic drug targets and could help to inform future stratified medicine innovations in mental health.

19.
Eur J Prev Cardiol ; 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33624048

RESUMO

AIMS : To investigate the population attributable fraction due to elevated lipoprotein (a) (Lp(a)) and the utility of measuring Lp(a) in cardiovascular disease (CVD) risk prediction. METHODS AND RESULTS : In 413 734 participants from UK Biobank, associations of serum Lp(a) with composite fatal/non-fatal CVD (n = 10 066 events), fatal CVD (n = 3247), coronary heart disease (CHD; n = 18 292), peripheral vascular disease (PVD; n = 2716), and aortic stenosis (n = 901) were compared using Cox models. Median Lp(a) was 19.7 nmol/L (interquartile interval 7.6-75.3 nmol/L). About 20.8% had Lp(a) values >100 nmol/L; 9.2% had values >175 nmol/L. After adjustment for classical risk factors, 1 SD increment in log Lp(a) was associated with a hazard ratio for fatal/non-fatal CVD of 1.12 [95% confidence interval (CI) 1.10-1.15]. Similar associations were observed with fatal CVD, CHD, PVD, and aortic stenosis. Adding Lp(a) to a prediction model containing traditional CVD risk factors in a primary prevention group improved the C-index by +0.0017 (95% CI 0.0008-0.0026). In the whole cohort, Lp(a) above 100 nmol/L was associated with a population attributable fraction (PAF) of 5.8% (95% CI 4.9-6.7%), and for Lp(a) above 175 nmol/L the PAF was 3.0% (2.4-3.6%). Assuming causality and an achieved Lp(a) reduction of 80%, an ongoing trial to lower Lp(a) in patients with CVD and Lp(a) above 175 nmol/L may reduce CVD risk by 20.0% and CHD by 24.4%. Similar benefits were also modelled in the whole cohort, regardless of baseline CVD. CONCLUSION : Population screening for elevated Lp(a) may help to predict CVD and target Lp(a) lowering drugs, if such drugs prove efficacious, to those with markedly elevated levels.

20.
Transl Psychiatry ; 9(1): 327, 2019 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-31797917

RESUMO

Anhedonia is a core symptom of several psychiatric disorders but its biological underpinnings are poorly understood. We performed a genome-wide association study of state anhedonia in 375,275 UK Biobank participants and assessed for genetic correlation between anhedonia and neuropsychiatric conditions (major depressive disorder, schizophrenia, bipolar disorder, obsessive compulsive disorder and Parkinson's Disease). We then used a polygenic risk score approach to test for association between genetic loading for anhedonia and both brain structure and brain function. This included: magnetic resonance imaging (MRI) assessments of total grey matter volume, white matter volume, cerebrospinal fluid volume, and 15 cortical/subcortical regions of interest; diffusion tensor imaging (DTI) measures of white matter tract integrity; and functional MRI activity during an emotion processing task. We identified 11 novel loci associated at genome-wide significance with anhedonia, with a SNP heritability estimate (h2SNP) of 5.6%. Strong positive genetic correlations were found between anhedonia and major depressive disorder, schizophrenia and bipolar disorder; but not with obsessive compulsive disorder or Parkinson's Disease. Polygenic risk for anhedonia was associated with poorer brain white matter integrity, smaller total grey matter volume, and smaller volumes of brain regions linked to reward and pleasure processing, including orbito-frontal cortex. In summary, the identification of novel anhedonia-associated loci substantially expands our current understanding of the biological basis of state anhedonia and genetic correlations with several psychiatric disorders confirm the utility of this phenotype as a transdiagnostic marker of vulnerability to mental illness. We also provide the first evidence that genetic risk for state anhedonia influences brain structure, including in regions associated with reward and pleasure processing.


Assuntos
Anedonia , Encéfalo/diagnóstico por imagem , Estudo de Associação Genômica Ampla , Transtornos Mentais , Herança Multifatorial , Adulto , Idoso , Anedonia/fisiologia , Estudos de Coortes , Bases de Dados Factuais , Feminino , Loci Gênicos/genética , Humanos , Imagem por Ressonância Magnética , Masculino , Transtornos Mentais/diagnóstico por imagem , Transtornos Mentais/genética , Transtornos Mentais/fisiopatologia , Pessoa de Meia-Idade , Herança Multifatorial/genética
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